Effects of Treatment of Impaired Glucose Tolerance orRecently Diagnosed Type 2 Diabetes With MetforminAlone or in Combination With Insulin Glargine on b-CellFunction: Comparison of Responses In Youth And AdultsThe RISE Consortium*

Diabetes 2019;68:1670–1680 | https://doi.org/10.2337/db19-0299

b-Cell dysfunction is central to the pathogenesis ofimpaired glucose tolerance (IGT) and type 2 diabetes.Compared with adults, youth have hyperresponsiveb-cells and their decline in b-cell function appears tobemore rapid. However, there are no direct comparisonsof b-cell responses to pharmacological interventionbetween the two age-groups. The Restoring Insulin Se-cretion (RISE) Adult Medication Study and the RISEPediatric Medication Study compared interventions toimprove or preserve b-cell function. Obese youth (n = 91)and adults (n = 132) with IGT or recently diagnosed type2 diabetes were randomized to 3 months of insulin glar-gine followed by 9 months of metformin, or 12 months ofmetformin. Hyperglycemic clamps conducted at base-line, after 12 months of medication, and 3 months aftermedication withdrawal assessed b-cell function assteady-state andmaximal C-peptide responses adjustedfor insulin sensitivity. Temporal changes in b-cell func-tion were distinctly different. In youth, b-cell functiondeteriorated during treatment and after treatment with-drawal, with no differences between treatment groups.In adults, b-cell function improved during treatment, butthis was not sustained after treatment withdrawal. Thedifference in b-cell function outcomes in response tomedications in youth versus adults supports a moreadverse trajectory of b-cell deterioration in youth.

The incidence and prevalence of type 2 diabetes haveincreased and reached alarming levels (1,2). These increasesare not limited to the adult population, as type 2 diabetesis becoming more common in youth during their second

decade of life (1), with an incidence in the U.S. that isprojected to triple over the next 40 years (2). The patho-genesis of type 2 diabetes in youth is poorly understood,and how it differs from that seen in adults is not known.

The Treatment Options for Type 2 Diabetes in Adoles-cents and Youth (TODAY) Study revealed that b-cell func-tion in youth-onset type 2 diabetes declined at a rate of20–35% per year, considerably accelerated compared withadult diabetes (3,4). This rapid decline resulted in progres-sive worsening of glycemic control even with good adher-ence to metformin and/or rosiglitazone (5). The TODAYStudy established b-cell dysfunction as a critical factor onthe path to the development of youth-onset type 2 diabetes.

The Restoring Insulin Secretion (RISE) Consortium wasestablished by the National Institute of Diabetes andDigestive and Kidney Diseases (NIDDK) to test approachesto preserve b-cell function in youth and adults withimpaired glucose tolerance (IGT) or recently diagnosedtype 2 diabetes. The RISE Pediatric Medication Studyand RISE Adult Medication Study were designed in tandemto allow for a direct comparison of the impact of phar-macological treatment on b-cell function, comparing met-formin alone with insulin glargine followed by metformin(the only medications approved by the U.S. Food and DrugAdministration for use in type 2 diabetes in youth). Anidentical hyperglycemic clamp protocol performed in bothstudies allowed for direct comparison of these treatmentsbetween youth and adults (6).

We have previously reported a number of importantand revealing differences between the youth and adultRISE study cohorts at baseline (7). Despite similar levels of

Corresponding author: Sharon L. Edelstein, rise@bsc.gwu.edu

Received 20 March 2019 and accepted 17 April 2019

Clinical trial reg. nos. NCT01779362 and NCT01779375, clinicaltrials.gov

This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db19-0299/-/DC1.

*A complete list of the RISE Consortium Investigators can be found in theSupplementary Data online.

© 2019 by the American Diabetes Association. Readers may use this article aslong as the work is properly cited, the use is educational and not for profit, and thework is not altered. More information is available at http://www.diabetesjournals.org/content/license.

1670 Diabetes Volume 68, August 2019

PHARMACOLOGY

AND

THERAPEUTIC

S

obesity and dysglycemia, obese youth with IGT or recentlydiagnosed type 2 diabetes 1) were markedly more insulinresistant than adults, 2) exhibited markedly augmentedb-cell responses to intravenously administered glucose andto the nonglucose secretagogue arginine, and 3) exhibitedaugmented b-cell responses even after accounting forinsulin sensitivity, suggesting that the workload on theirb-cells is greater than that observed in adults. Further, wehave reported that the RISE treatments failed to haltprogressive b-cell failure over time in youth (8). Thesefundamental metabolic differences described betweenyouth and adults at baseline, together with the poorresponse to both metformin alone or insulin glarginefollowed by metformin in youth, suggest potential differ-ences between youth and adults in the pathogenesisand/or time course of b-cell failure.

Here we test the hypothesis that youth and adultsrespond differently to identical pharmacological treat-ments targeting b-cell function. To address this hypoth-esis, the following key questions were posed: 1) Do theeffects of glargine followed by metformin or metforminalone on b-cell function differ between youth and adults?and 2) Are changes in b-cell function following 12 monthsof active treatment more durable in adults comparedwith youth when assessed 3 months after treatmentwithdrawal?

RESEARCH DESIGN AND METHODS

Study ProtocolsThe RISE Pediatric Medication Study and RISE AdultMedication Study were randomized, partially blinded clin-ical trials. The rationale and methods have been describedin detail previously (6,9) and the study protocol is availableonline at https://rise.bsc.gwu.edu/web/rise/collaborators.Each participating center’s institutional review board (IRB)approved the appropriate protocol. Consistent with theDeclaration of Helsinki and each center’s IRB guidelines,written informed consent or assent was obtained fromeach participant.

Participants

Screening and Eligibility: YouthYouth aged 10–19 years with pubertal development at orbeyond Tanner stage II at high risk for IGT or with recentlydiagnosed type 2 diabetes were screened with a medicalhistory, physical examination, and additional laboratorytests for purposes of inclusion/exclusion (8). A BMI in the85th percentile or greater for age and sex with a maximumBMI #50 kg/m2 was required. A screening 75-g oralglucose tolerance test (OGTT) and hemoglobin A1c

(HbA1c) were obtained. If drug naive, an OGTT witha fasting plasma glucose $5 mmol/L, 2-h glucose $7.8mmol/L, and HbA1c #8.0% (#64 mmol/mol) were re-quired. The HbA1c criteria for youth with type 2 diabetesalready taking metformin were#7.5% (#58 mmol/mol) ifonmetformin for,3months and#7.0% (#53mmol/mol)

if on metformin for 3–6 months. Testing negative for GADand IA2 autoantibodies was also required.

Screening and Eligibility: AdultsAdults were similarly screened with a medical history, phys-ical examination, and laboratory tests for inclusion/exclusion(10). Eligibility criteria included age 20–65 years and BMI$25 kg/m2 ($23 kg/m2 for Asian Americans) but ,50kg/m2. A screening 75-g OGTT and HbA1c were obtained.Eligibility required a fasting glucose 5.3–6.9 mmol/L, OGTT2-h glucose $7.8 mmol/L, and HbA1c #7.0%(#53 mmol/mol). Adults with known IGT or diabetesfor ,1 year were eligible if they had never receivedglucose-lowering medications and otherwise qualified.

For both groups, final eligibility for the study re-quired $80% compliance with 3 weeks of oral placebomedication and placebo injection. Eligible participantsunderwent a baseline 3-h OGTT and two-step hyperglyce-mic clamp, followed by random treatment assignmentstratified by study site. Pediatric and adult participantswere randomized to glargine for 3 months followed bymetformin for 9 months, or to metformin alone for12 months. Additional adults were also randomized totwo other arms that were not part of the study in youthand therefore are not included in this report.

InterventionsAdult participants randomized to metformin alone re-ceived double-blinded tablet assignment, while metforminwas unmasked in youth. Titration of medication took placeover 4 weeks, starting at a dose of 500 mg once daily, toa maximum dose of 1,000 mg twice daily. Participantsunable to tolerate a given dose increment were reverted tothe highest previously tolerated dose.

The insulin glargine followed by metformin group re-ceived 3 months of insulin glargine titrated at least twiceweekly by a preset algorithm (8,10) to achieve a fastingglucose of 4.4–5.0 mmol/L on the basis of daily self-monitored blood glucose. This was followed immediatelyby 9 months of metformin (titrated to 1,000 mg twicedaily). Youth already taking metformin and randomized toinsulin glargine therapy discontinued active metformin atthe time of initiation of insulin glargine treatment.

Participants took their assigned intervention for12 months, after which it was withdrawn, and follow-upcontinued while off study medication for 3 months todetermine the 15-month coprimary outcomes.

Participants returned to the clinic every 3 months fordetermination of medication adherence and assessment ofadverse events. Metformin adherence was determined bythe pill count in the returned medication bottle, andinsulin glargine adherence was based on the residualvolume of fluid in the pen. If HbA1c safety thresholdswere exceeded at any visit, outcome assessments wereperformed whenever possible before instituting rescuetherapy. Safety was monitored by an independent dataand safety monitoring board.

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Procedures and Calculations

AnthropometricsAnthropometric measurements were obtained with par-ticipants wearing light clothing without shoes. Waistcircumference, height, and weight were measured withstandard methods as previously described (8).

Hyperglycemic ClampAfter a 10-h overnight fast, a two-step hyperglycemic clampwas performed with goal glucose levels of 11.1 mmol/Lfollowed by $25 mmol/L, the latter representing maxi-mal glycemic potentiation and at which the nonglucosesecretagogue arginine was administered (7). Briefly, tar-get glucose levels were achieved using boluses and a vari-able rate intravenous infusion of 20% dextrose, the ratebased on a computerized algorithm developed by theConsortium, combined with bedside glucose monitoring.Arterialized blood samples were obtained prior to and at2, 4, 6, 8, 10, 30, 60, 90, 100, 110, and 120 min afterstarting the glucose infusion; the final three samples wereused to define the steady-state interval for the firststep (11.1 mmol/L) target. For the second step, aftera minimum of an additional 15 min with glucose lev-els .25 mmol/L, the response to hyperglycemia plusarginine was determined using blood samples drawn5 and 1 min prior to and 2, 3, 4 and 5 min after bolusinjection of arginine (5 g).

Hyperglycemic Clamp–Derived MeasuresInsulin Sensitivity. Insulin sensitivity (M/I) was quantifiedas the mean of the glucose infusion rate at 100, 110, and120 min of the clamp, expressed as per kilogram of bodyweight and corrected for urinary glucose loss (M), dividedby the mean steady-state plasma insulin concentration (I)at these same time points. Urinary glucose loss was de-termined as the product of the measured urinary glucoseconcentration and urinary volume (7).C-Peptide Responses. The acute (first-phase) C-peptideresponse to glucose (ACPRg) was calculated as the meanincremental response above baseline (average of 210and 25 min) from samples drawn at 2, 4, 6, 8, and10 min following glucose administration (7).

Steady-state (second-phase) C-peptide levels were cal-culated as the mean C-peptide concentrations at 100, 110,and 120 min of the hyperglycemic clamp (7).

The acute C-peptide response to arginine at maximalglycemic potentiation (ACPRmax; .25 mmol/L) was cal-culated as the mean concentrations in samples drawn 2, 3,4, and 5 min after arginine injection minus the average ofconcentration of the samples obtained 1 and 5min prior toarginine administration (7).

AssaysAfter sampling, all blood samples were immediately placedon ice, separated, frozen, and stored at 280°C. Frozensamples were shipped overnight to the central biochem-istry laboratory at the University of Washington for assay

of glucose, insulin, and C-peptide concentrations usingmethods previously described (7).

Statistical AnalysesData were collected centrally, and analyses were performedaccording to a prespecified analysis plan. For these proof-of-principle trials, we chose two measures of b-cell func-tion as coprimary outcomes: clamp-derived steady-stateC-peptide and ACPRmax at 15 months, both evaluatedjointly with M/I (6,8,10). Clamp-derived ACPRg was eval-uated as a secondary outcome.

The prespecified primary analysis was the comparisonof b-cell responses paired with M/I between treatmentgroups at month 15 of the study (i.e., 3 months aftertreatment withdrawal), adjusted for baseline b-cell re-sponse and M/I. This provides a treatment group com-parison of the durability effect after treatment withdrawal.Major secondary analyses compared treatment groupswithin each study at the end of active intervention,12 months. Joint models for b-cell response and M/Iwere fit simultaneously using seemingly unrelated regres-sion techniques (11–13), which provide a 2-DF x2 test ofthe treatment arm difference in the joint values of b-cellresponse and M/I between treatment groups within study.All models used natural logarithmically transformed in-sulin sensitivity (M/I) and b-cell response variables due tothe skewed distribution of these data. Prior to taking logs,a constant of 1.06 was added to the ACPRg because ofnegative values in this b-cell response variable. Two youthparticipants randomized to metformin had HbA1c levelsthat required treatment during the active intervention.These participants successfully completed the 12-monthvisit before being withdrawn from the study. Their data areincluded through 12 months. Imputing worst-case valuesat 15-months for these participants did not appreciablyalter the results; these results are not presented further.

The Hotelling T2 method was used to simultaneouslytest changes in b-cell responses and M/I within eachtreatment group over time (13). Glucose and C-peptideconcentrations across study and treatment groupsthroughout the hyperglycemic clamp were compared usingt tests. Percent changes from baseline across study withintreatment arm in b-cell responses and M/I were comparedusing the nonparametric Kruskal-Wallis test due to theirskewed distributions. Changes from baseline in BMI andHbA1c were compared across study within each treatmentarm at specific time points using t tests.

RESULTS

Baseline Demographic, Physical, and MetabolicCharacteristics of Youth and Adults by TreatmentGroupsAdults assigned to insulin glargine plus metformin weresimilar in age to those assigned to metformin alone,whereas youth assigned to the metformin alone groupwere slightly younger than those assigned to insulinglargine followed by metformin, but similar in Tanner

1672 b-Cell Response to Pharmacological Intervention Diabetes Volume 68, August 2019

stage (Table 1). Notably, the pediatric study includeda larger proportion of females and of nonwhite partici-pants than the adult study. In both treatment groups,youth and adults had similar body weight and BMI,whereas the waist-to-hip ratio was higher in adults com-pared with youth in both treatment arms. Systolic anddiastolic blood pressures were higher in adults as was theuse of blood pressure–lowering medication. HbA1c and theproportion of participants with IGT were similar amongadults and youth and across treatment arms.

Although fasting glucose concentrations were similar inadults and youth across treatment arms, fasting insulinand C-peptide concentrations were significantly higher inyouth (P , 0.001) (Table 2). Notably, all b-cell responsemeasures were significantly higher in youth in both treat-ment arms, reflecting their profound insulin resistance, asquantified by M/I, and b-cell hyperresponsiveness. Insulinclearance, defined as the ratio of fasting C-peptide tofasting insulin (6), was significantly lower in youth com-pared with adults (P , 0.001).

Plasma Glucose and C-Peptide Concentrations Duringthe Hyperglycemic Clamp in Youth and Adults byTreatment ArmPlasma glucose and C-peptide concentrations during thetwo-step hyperglycemic clamp are illustrated at baseline,

12 months (on treatment), and 15 months (3 months afterwithdrawal of treatment) for each treatment arm in youthand adults (Fig. 1). Of note, identical target glucose con-centrations of 11.1 and .25 mmol/L (i.e., stimuli drivingthe b-cell response) were achieved between treatmentgroups, over time, and between youth and adults. Despitethese matched clamped glucose levels and with treatmentinterventions, at all time points during the clamp,C-peptide concentrations were higher in youth than adults(all P , 0.001). Within each age-group, there were nosignificant treatment group differences on either glucoseor C-peptide.

Treatment Effects on Hyperglycemic Clamp–DerivedInsulin Sensitivity and b-Cell Responses From Baselineto 12 and 15 MonthsWe used vector plots to better illustrate concurrentchanges in the hyperglycemic clamp–derived b-cellresponses (steady-state C-peptide, ACPRmax, and ACPRg)expressed jointly with M/I. In Fig. 2, for each age-group,the mean value at baseline is indicated by the black boxwith a 0 (i.e., month 0). The dashed lines from the boxes atmonths 12 and 15 indicate the trajectory of mean valuesfrom baseline to 12 months of intervention and thento 3 months after discontinuation of the intervention(15 months) for insulin glargine followed by metformin

Table 1—Baseline characteristics by treatment group

Glargine followed by metformin Metformin alone

Adult Youth Adult YouthN 5 67 N 5 44 N 5 65 N 5 47 P value

AnthropometricsAge (years) 53.5 6 9.3 14.9 6 2.0 55.2 6 8.2 13.9 6 2.1 ,0.001Female 23 (34.3) 27 (61.4) 37 (56.9) 38 (80.9) ,0.001Race/ethnicity ,0.001White 37 (55.2) 13 (29.5) 34 (52.3) 12 (25.5)Black 21 (31.3) 14 (31.8) 19 (29.2) 9 (19.1)Hispanic (any) 5 (7.5) 14 (31.8) 6 (9.2) 20 (42.6)Other 4 (6.0) 3 (6.8) 6 (9.2) 6 (12.8)

Weight (kg) 104.4 6 20.0 102.0 6 25.7 98.1 6 18.6 97.7 6 23.3 0.274BMI (kg/m2) 35.0 6 5.9 36.5 6 6.4 35.0 6 5.1 36.9 6 6.4 0.201BMI percentile 98.4 6 2.5 98.8 6 1.3 0.297Waist-to-hip ratio 0.97 6 0.07 0.93 6 0.08 0.95 6 0.08 0.94 6 0.07 0.029Systolic BP (mmHg) 127.7 6 12.0 120.7 6 7.8 127.1 6 13.3 119.5 6 8.7 ,0.001Diastolic BP (mmHg) 78.7 6 9.5 67.6 6 7.7 77.8 6 11.1 70.1 6 7.9 ,0.001BP-lowering medication use (yes) 34 (50.7) 1 (2.3) 35 (53.8) 2 (4.3) ,0.001

Metabolic phenotypeHbA1c (%) 5.80 6 0.33 5.73 6 0.60 5.77 6 0.40 5.68 6 0.57 0.561HbA1c (mmol/L) 39.9 6 3.6 39.2 6 6.5 39.5 6 4.3 38.6 6 6.3 0.561IGT 50 (74.6) 26 (59.1) 49 (75.4) 28 (59.6) 0.105

LipidsTotal cholesterol (mmol/L) 4.21 6 0.96 3.86 6 0.91 4.51 6 0.94 3.72 6 0.65 ,0.001LDL cholesterol (mmol/L) 2.41 6 0.77 2.25 6 0.80 2.68 6 0.81 2.08 6 0.63 ,0.001Triglycerides (mmol/L) 1.36 [0.58, 3.20] 1.11 [0.39, 3.14] 1.28 [0.50, 3.28] 1.17 [0.45, 3.06] 0.314HDL cholesterol (mmol/L) 1.12 6 0.24 1.02 6 0.25 1.17 6 0.30 1.04 6 0.21 0.007Lipid-lowering medication use (yes) 31 (46.3) 1 (2.3) 20 (30.8) 0 (0.0) ,0.001

Data are n (%), mean 6 SD, or geometric mean [95% CI]. P values for nonnormally distributed data based on log-transformed values.P value for ANOVA Type III F test. “Other” for race/ethnicity includes mixed, Asian, American Indian, and other. BP, blood pressure.

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(green) and metformin alone (brown). Values above theblack line represent improved b-cell function, and val-ues below the line represent a decline in b-cell function.The ellipses depict the 95% confidence bands aroundthe boxes (group mean values) at months 12 and15. There are a number of major differences betweenyouth and adults, not only at baseline but notably inthe temporal changes in b-cell responses during theinterventions.

In the pediatric group, as previously reported (8), nosignificant differences were found between treatmentgroups at 12 or 15 months in either primary measureof b-cell function (steady-state C-peptide or ACPRmax,each paired with M/I) or in the secondary measure of b-cell function (ACPRg paired with M/I) (Fig. 2A, C, and E).Further, b-cell responses declined from baseline to12 months and from 12 to 15 months in both treatmentgroups. These changes indicate a failure of both interven-tions to improve or halt the rapid deterioration of b-cellfunction in youth.

In contrast, as recently reported (10), in adults after12 months of treatment, ACPRg significantly improvedin both treatment groups, M/I increased slightly inthe metformin group, and no significant changeswere observed in steady-state C-peptide or ACPRmaxin either group (Fig. 2B, D, and F). The changes inACPRg combined with M/I represent improved b-cellfunction during active treatment. At 15 months,3 months after treatment withdrawal, all responsemeasures combined with M/I were not different fromthe baseline curve. Further, no b-cell response measurepaired with M/I differed between treatment groups at12 or 15 months. Importantly, the marked progressivedeterioration seen in b-cell function in youth duringtreatment and after discontinuing treatment was not ob-served in adults.

Youth Versus Adults Comparisons of Percent Changesin Hyperglycemic Clamp–Derived Insulin Sensitivity andb-Cell Responses Over TimeFigure 3 compares the percent changes in youth and adultsin hyperglycemic clamp–derived insulin sensitivity and thetwo primary b-cell response measures by treatment armfrom baseline to 12 and 15 months.

M/IAlthough modest improvements were seen in insulinsensitivity in both youth and adults in each treatmentarm, the percent change in M/I in adults and youth wasnot significantly different in either treatment arm at both12 and 15 months.

Steady-State C-PeptideIn the insulin glargine followed by metformin group,the percent decrease in steady-state C-peptide frombaseline to 12 months and to 15 months was signifi-cantly greater in youth than in adults (P = 0.004 and P =0.024, respectively). In the metformin alone group, thepercent decline in steady-state C-peptide at both 12and 15 months was not significantly different betweenyouth and adults.

ACPRmaxThe values for ACPRmax were numerically lower at 12 and15 months in both treatment arms in each age-group.However, the percent reduction was only significantlygreater in youth than adults at 12 months in the insulinglargine followed by metformin arm (P , 0.001).

Youth Versus Adults Comparisons of Percent Changesin BMI and HbA1c Over TimeFigure 4 illustrates percent change in BMI and HbA1c

from baseline to months 3, 6, 9, 12, and 15. The changein BMI was significantly different between youth and

Table 2—Metabolic phenotypes and clamp-derived measures of b-cell function and insulin sensitivity at baseline by treatmentgroup

Glargine followed by metformin Metformin alone

Adult Youth Adult YouthN 5 67 N 5 44 N 5 65 N 5 47 P value

Fasting glucose (mmol/L) 6.1 6 0.5 6.0 6 0.9 6.1 6 0.6 6.1 6 1.1 0.311

Fasting C-peptide (nmol/L) 1.242 6 0.471 1.627 6 0.552 1.206 6 0.430 1.820 6 0.581 ,0.001

Fasting insulin (pmol/L) 109.2 [40.2, 296.8] 211.1 [54.8, 813.5] 102.9 [36.8, 287.8] 247.4 [74.1, 825.4] ,0.001

Steady-state (second-phase) C-peptideresponse (nmol/L) 4.0 [1.9, 8.4] 5.2 [2.4, 11.2] 3.9 [2.0, 7.6] 5.1 [2.3, 11.2] ,0.001

ACPRmax (nmol/L) 4.8 [1.8, 12.5] 7.3 [3.3, 16.2] 4.8 [2.0, 11.7] 8.1 [3.4, 9.3] ,0.001

ACPRg (nmol/L) 1.7 [1.0, 3.2] 2.4 [0.9, 6.4] 1.8 [1.0, 3.2] 2.3 [0.8, 6.4] ,0.001

Glucose disposal rate (M; mmol/kg/min) 0.021 6 0.010 0.025 6 0.013 0.022 6 0.009 0.023 6 0.010 0.209

M/I (mmol/kg/min per pmol/L) 2.8 [0.7, 12.1] 1.6 [0.3, 7.4] 3.3 [0.8, 13.1] 1.5 [0.4, 6.8] ,0.001

Fasting C-peptide/fasting insulin(310 nmol/pmol) 1.06 [0.62, 1.81] 0.73 [0.29, 1.87] 1.10 [0.59, 2.06] 0.70 [0.28, 1.77] ,0.001

Data are mean 6 SD or geometric mean [95% CI]. P values for nonnormally distributed data based on log-transformed values. P valuefor ANOVA Type III F test.

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adults in the insulin glargine followed by metforminarm, with BMI decreasing starting at month 6 in adultsbut not youth (P , 0.05 at all time points in adultsvs. youth). In the metformin alone arm, BMI decreasedat all times in adults and in youth through month 12,with no significant differences between youth andadults.

In the insulin glargine followed by metformin arm, therelative decline in HbA1c from baseline to month 6 wassignificantly greater in youth than adults (P = 0.046), withHbA1c change from baseline to all other time points(months 3, 9, 12, and 15) not significantly differentbetween youth and adults (P . 0.1 at all time points).There were no significant differences in the relative changein HbA1c from baseline between youth and adults in themetformin alone arm.

DISCUSSION

These analyses of the RISE medication studies providethe first direct comparisons in youth and adults of the

effect of medication interventions targeting improvedb-cell function. The effects of metformin alone or insulinglargine followed by metformin on insulin sensitivity andtheir ability to preserve or restore b-cell function werequantified at the end of 12 months of treatment andagain at 15 months, the latter time point at whichinterventions had been withheld for 3 months. Thehyperglycemic clamp provided an assessment of b-cellresponses to glucose as well as arginine, a nonglucosesecretagogue, in relation to insulin sensitivity. Withineach age-group, the two interventions did not differ intheir effects on b-cell function. Importantly however,unlike adults, youth did not have improved or preservedb-cell function at 12 months (during active treatment).Furthermore, following withdrawal of the study treat-ments, there was a steep and progressive decline in b-cellfunction in the pediatric group indicated by the down-ward shift in their vector plot relative to the baselinecurvilinear relationship between insulin sensitivity andC-peptide responses.

Figure 1—Glucose and C-peptide concentrations during the hyperglycemic clamp. Glucose and C-peptide concentrations from thehyperglycemic clamps at baseline, after 12months of treatment (Month 12), and 3months after discontinuing the intervention (Month 15). Thegoal steady-state glucose targets were 11.1 mmol/L between 90 and 120 min and .25 mmol/L at 150 min. Data are displayed as mean 6SEM.

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Although a decline in b-cell function also occurs in adultswith type 2 diabetes, this process is accelerated in youth(3,4). The TODAY Study showed that the rate of loss ofglycemic control on metformin monotherapy approximated50%, suggesting that b-cell failure may be more rapid inyouth than in adults (5,14). Until now this comparison hasbeen merely speculative as no prior study has performeda head-to-head comparison between youth and adults withthe same levels of dysglycemia and duration of diseasestudied under similar prospective conditions.

Contrary to our original hypothesis, in RISE we havefound that early intervention with insulin glargine was notassociated with any improvement in b-cell function inyouth with IGT or early diagnosed type 2 diabetes (8).Further, while the decline in b-cell function was greater inyouth than adults, in RISE we failed to replicate thepreviously reported effect of,2 weeks of intensive insulintherapy in recently diagnosed Chinese patients with type2 diabetes to improve b-cell function 1 year later (15). Thereason(s) for these differences across the two age-groups

Figure 2—Vector plots illustrating the treatment effects on concurrent model-based changes from baseline to 12 and 15 months inhyperglycemic clamp–derived insulin sensitivity and b-cell responses in youth and adults. The figures depict the relationships in youth (A, C,and E) and adults (B, D, and F ) of the two coprimary outcomes and secondary outcome: hyperglycemic clamp–derived b-cell responses(steady-state C-peptide, ACPRmax, and ACPRg), each paired with M/I, at baseline, 12 months, and 15 months, in green for the insulinglargine followed by metformin and in brown for metformin alone. The black line depicts the joint relationship between b-cell response andM/I at baseline for the full cohort within each study, with the mean value at baseline for the full cohort indicated by the black box with a 0. Thedotted lines to boxes at months 12 and 15 show the trajectory of values from baseline to 12 months of intervention and then to 3 monthsafter discontinuation of the intervention (15 months). Values above the black line represent improved b-cell function; values belowthe line represent poorer b-cell function. The ellipses depict the 95% confidence bands around the points at months 12 and 15.

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remain unclear, but they do suggest that even resting theb-cell for 3 months in youth does not slow the rate of declinein b-cell function to render it similar to that in adults. It isimportant to note the difference in insulin interventionsused by Weng et al. (15) from that employed in RISE. Wenget al. provided intensive insulin therapy either as a continuoussubcutaneous insulin infusion or multiple daily insulin injec-tions, while in RISE insulin was administered as a once-dailyinjection based on the fasting glucose level.

The current data from RISE not only confirm the poorefficacy of metformin as a treatment for hyperglycemia inobese adolescents (5) but also demonstrate that whencompared with adults, youth have a greater decline inb-cell function over time both while on treatment aswell as after metformin withdrawal. Interestingly, after12 months of metformin, adults demonstrated improve-ment or maintenance in the acute and steady-stateresponses to glucose, while youth did not. This improve-ment in b-cell function in adults while receiving metfor-min is in keeping with that observed with oral glucoseadministration in adults being studied for the effects of the

medication to prevent diabetes or produce durable glycemiccontrol in recently diagnosed type 2 diabetes (4,16).

The C-peptide response to arginine at maximal glycemicpotentiation (ACPRmax) also declined in youth with bothtreatments; the same changes were not exhibited in adults.This measure, an estimate of b-cell secretory capacity (17),has previously been suggested to provide an estimate ofb-cell mass in animal models and in humans after isletautotransplantation (18). However, it should be kept inmind that this measure can also change fairly rapidly ina time interval that would not be compatible with a changein b-cell mass (19,20). Whether the decline in b-cellsecretory capacity in RISE youth reflects a reduction inb-cell mass or an alteration in molecular aspects of cellularfunction that is more severe than observed in adults is notcertain and warrants further investigation. Understandingsuch would be important, as it will likely have an impacton the selection of future approaches to preserve b-cellfunction in youth and possibly in adults.

In the current analysis, each clamp-derived b-cell re-sponse measure was expressed as a function of insulin

Figure 3—Comparison of percent changes from baseline to 12 and 15 months in hyperglycemic clamp–derived insulin sensitivity and b-cellmeasures in youth vs. adults. Shown in shades of green are data from the insulin glargine followed bymetformin arm (dark green, adults; lightgreen, youth). Shades of brown are data from the metformin alone arm (dark brown, adults; light brown, youth). The bars indicate 95% CI.

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sensitivity, as depicted in Fig. 2. Notably, the location ofthe baseline curve was distinctly different in the two age-groups, as were the responses to the interventions andtheir subsequent withdrawal. The combined measure atbaseline in youth was leftward and upward shifted com-pared with adults (Fig. 2A, C, and E in youth vs. Fig. 2B, D,and F in adults). It is conceivable that the initial positionalong this curve may have influenced the effects of themedications used in this study to affect the progression ofb-cell failure. The precise mechanisms that underlie theprofound differences in insulin sensitivity and responsive-ness of the b-cell observed between youth and adults duringand after treatment are not clearly evident.

It is plausible that the pathophysiology of dysglycemiain youth is driven by more severe hepatic and adiposetissue insulin resistance, both of which are potentiallyrelated to the obesity and the co-occurrence of fatty liver(21,22). Studies from the Arslanian group (23,24) showedthat obese youth with normal glucose tolerance have 32–45% higher fasting glycerol turnover compared with thatreported in obese adults. We have not assessed hepatic andadipose tissue insulin sensitivity, and therefore furtherstudies are needed to determine their potential role asa modulator of b-cell function in youth with IGT andrecently diagnosed type 2 diabetes. Future studiesshould evaluate lipid metabolism between phenotypicallymatched adults and youth along the spectrum of glucosetolerance. Puberty is another potential factor in the pro-found reduction in insulin sensitivity seen in RISE youth.

While .60% of participants were already Tanner stage V(8), puberty is known to be characterized by an ;30%reduction in whole-body insulin sensitivity and increasedb-cell function in nonoverweight adolescents (25,26),which is exaggerated by the presence of obesity (27).When this insulin resistance of puberty wanes is notwell understood.

Strengths in RISE are the robust approach to quanti-fication of insulin sensitivity and b-cell responses to bothglucose and the nonglucose secretagogue arginine in bothyouth and adults, thus providing mechanistic insights intohow the tested interventions affected two key metabolicdefects of type 2 diabetes: insulin sensitivity and b-cellresponses. The enrollment of the pediatric group and useof both the same interventions and the same study par-adigm has allowed, for the first time, comparative analysisof multiple outcomes across the life span. There are alsosome limitations to this study. First, we did not use thehyperinsulinemic-euglycemic clamp coupled with stableisotope measures of hepatic glucose production and insulinsuppressive effects of lipolysis; this would have addedadditional information regarding the tissue-specificresponses to insulin and of potential differences betweenyouth and adults. Second, the waist-to-hip ratio differedmarginally between age-groups, but we did not directlyquantify body fat distribution or hepatic fat content toevaluate possible contributions to the greater insulin re-sistance in youth. Third, in some instances we clearlyobserved differences between youth and adults, although

Figure 4—Comparison in the temporal changes in BMI and HbA1c from baseline in youth vs. adults. Shown in shades of green are data fromthe insulin glargine followed by metformin arm (dark green, adults; light green, youth). Shades of brown are data from the metformin alonearm (dark brown, adults; light brown, youth). The bars indicate 95% CI. The asterisks represent visits where changes were significantlydifferent in youth vs. adults (P , 0.05).

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these did not reach statistical significance because of therelatively small sample sizes.

In conclusion, we describe the underlying pathophysi-ological mechanisms explaining the lack of effects of eithermetformin alone or insulin glargine followed bymetforminon improving the relationship between insulin sensitivityand b-cell function (i.e., reducing b-cell secretory demand)in youth compared with adults with similar degrees ofobesity and dysglycemia. The inability of these two treat-ments to reduce b-cell secretory demand contrasts withthat in adults in whom a modest improvement in b-cellfunction occurred with metformin. These findings rein-force a need for mechanistic studies to further explore thepathophysiology and identify other interventions or med-ications that alone or in combination could successfullycombat the insulin resistance and progressive loss of b-cellfunction that leads to IGT and type 2 diabetes.

APPENDIX

Writing Group. Sonia Caprio (chair), David A. Ehrmann(co-chair), Sharon L. Edelstein, Kieren J. Mather, Silva A.Arslanian, Mark T. Tripputi, Kristen J. Nadeau, Ellen W.Leschek, Thomas A. Buchanan, and Steven E. Kahn.

Acknowledgments. The RISE Consortium acknowledges the supportand input of the RISE Data and Safety Monitoring Board; Barbara Linder, theNIDDK program official for RISE; and Peter Savage, who served as the scientificofficer for RISE prior to his retirement. The Consortium is also grateful to theparticipants who, by volunteering, are furthering our ability to reduce the burdenof diabetes.Funding. RISE was supported by grants from the National Institutes of Health(NIH) (NIDDK U01DK-094406, U01DK-094430, U01DK-094431, U01DK-094438, U01DK-094467, P30DK-017047, P30DK-020595, P30DK-045735,and P30DK-097512 and National Center for Advancing Translational SciencesUL1TR-000430, UL1TR-001082, UL1TR-001108, UL1TR-001855, UL1TR-001857, UL1TR-001858, and UL1TR-001863), the Department of VeteransAffairs, and Kaiser Permanente Southern California. Additional financial andmaterial support from the American Diabetes Association, Allergan Corporation,Apollo Endosurgery, Abbott Laboratories, and Novo Nordisk A/S is gratefullyacknowledged.Duality of Interest. S.E.K. and S.A.A. serve as paid consultants on advisoryboards for Novo Nordisk. S.E.K. is a member of a steering committee for a NovoNordisk–sponsored clinical trial. K.J.M. held an investigator-initiated researchgrant from Novo Nordisk during the performance of this study. S.A.A. is aninvestigator in a Novo Nordisk–sponsored clinical trial. T.A.B. has receivedresearch support from Allergan Corporation and Apollo Endosurgery. No otherpotential conflicts of interest relevant to this article were reported.Author Contributions. The steering committee (principal investigator ateach site, the data coordinating center, and the NIDDK project scientist) designedand implemented the study. All writing group members performed the research.S.L.E. and M.T.T. performed all data analysis. S.C. wrote the first draft, and allothers contributed to the discussion and edited the manuscript. S.C., S.L.E., andS.E.K. are the guarantors of this work and, as such, had full access to all the datain the study and take responsibility for the integrity of the data and the accuracy ofthe data analysis.Data and Resource Availability. In accordance with the NIH PublicAccess Policy, we continue to provide all manuscripts to PubMed Central includingthis manuscript. RISE has provided the protocols to the public through its publicwebsite (https://www.risestudy.org). The RISE Consortium abides by the NIDDK

data sharing policy and implementation guidance as required by the NIH/NIDDK(https://www.niddkrepository.org/studies/rise/).Prior Presentation. Parts of this study were presented in abstract form atthe 79th Scientific Sessions of the American Diabetes Association, San Francisco,CA, 7–11 June 2019.

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